RESUMO
Ebstein anomaly is a rare congenital heart disease that has been described in domestic dogs, a meerkat, a pygmy goat, and a lion. An 11-mo-old Tsushima leopard cat presented to Osaka Prefecture University Veterinary Hospital for diagnosis and treatment of right-sided congestive heart failure. Echocardiography showed a dilated right atrium and ventricle with an enlarged tricuspid valve annulus and apical displacement of the tricuspid valve leaflets. The cat was diagnosed with Ebstein anomaly. To the best of our knowledge, this is the first report of this type of congenital heart disease in a Tsushima leopard cat.
Assuntos
Anomalia de Ebstein/patologia , Felidae , Animais , Fármacos Cardiovasculares/uso terapêutico , Anomalia de Ebstein/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/veterinária , MasculinoRESUMO
Mas-related G-protein coupled receptor member D (MRGPRD) is a G protein-coupled receptor (GPCR) which belongs to the Mas-related GPCRs expressed in the dorsal root ganglia (DRG). In this study, we investigated two novel ligands in addition to beta-alanine: (1) beta-aminoisobutyric acid, a physiologically active substance, with which possible relation to tumors has been seen together with beta-alanine; (2) diethylstilbestrol, a synthetic estrogen hormone. In addition to the novel ligands, we found that transfection of MRGPRD leads fibroblast cells to form spheroids, which would be related to oncogenicity. To understand the MRGPRD novel character, oncogenicity, a large chemical library was screened in order to obtain MRGPRD antagonists to utilize in exploring the character. The antagonist in turn inhibited the spheroid proliferation that is dependent on MRGPRD signaling as well as MRGPRD signals activated by beta-alanine. The antagonist, a small-molecule compound we found in this study, is a potential anticancer agent.
Assuntos
Ácidos Aminoisobutíricos/química , Dietilestilbestrol/química , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Esferoides Celulares/citologia , Esferoides Celulares/metabolismo , beta-Alanina/química , Animais , Sítios de Ligação , Células HEK293 , Humanos , Ligantes , Camundongos , Células NIH 3T3 , Ligação ProteicaRESUMO
BACKGROUND: Velocity ratio, velocity time integral (VTI) ratio, and pulmonary valve area indexed to body surface area (iPVA) are methods of assessment of pulmonary valve stenosis (PS) severity that are less dependent on blood flow. Studies evaluating these methods are limited. OBJECTIVES: To determine the effects of butorphanol, atenolol, and balloon valvuloplasty (BV) on velocity ratio, VTI ratio, iPVA, mean PG, and max PG. ANIMALS: Twenty-seven dogs with PS (max PG >50 mm Hg). METHODS: Prospective study. All dogs underwent an echocardiogram at baseline, 5-minutes after administration of butorphanol (0.2-0.25 mg/kg IV), and 2-to-4 weeks after atenolol (1-1.5 mg/kg q12h). Twenty-one of these were evaluated 24-hours after BV. RESULTS: There were no significant differences (P > .05) amongst any of the methods of assessment of PS severity after butorphanol. After atenolol, mean (SD) of mean (57.0 [21.0] mm Hg) and max PG (93.1 [33.8] mm Hg) were significantly decreased (P ≤ .047) compared with baseline (65.2 [26.2] mm Hg and 108 [44.4] mm Hg, respectively). After atenolol, there were no significant (P ≥ .12) differences in velocity ratio (0.29 [0.09]), VTI ratio (0.18 [0.05]), or iPVA (0.43 [0.16] cm2 /m2 ) compared with baseline (0.30 [0.09], 0.19 [0.09], 0.44 [0.17] cm2 /m2 , respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Atenolol might reduce mean and max PG but does not alter less flow-dependent methods of assessment of PS severity (velocity ratio, VTI ratio, and iPVA) in dogs with PS. Results support an integrative approach to assessment of PS severity that includes less flow-dependent methods, particularly in states of altered flow or right ventricular function.
Assuntos
Doenças do Cão/diagnóstico por imagem , Ecocardiografia Doppler , Estenose da Valva Pulmonar/veterinária , Valva Pulmonar/diagnóstico por imagem , Animais , Valvuloplastia com Balão/veterinária , Cães , Feminino , Masculino , Estudos Prospectivos , Valva Pulmonar/patologia , Estenose da Valva Pulmonar/diagnóstico por imagem , Estenose da Valva Pulmonar/patologia , Estenose da Valva Pulmonar/terapiaRESUMO
BACKGROUND: Sotalol is a commonly used antiarrhythmic drug that may alter ventricular function. OBJECTIVE: To determine the effect of sotalol on echocardiographic indices of ventricular systolic function in dogs with ventricular arrhythmias. ANIMALS: Thirty-five client-owned dogs with ventricular arrhythmias. METHODS: Dogs with ventricular arrhythmias (n = 27) had an echocardiogram and 5-minute ECG performed at baseline and 2-4 hours post-sotalol (2-2.5 mg/kg PO once). Eight additional dogs underwent the same protocol but did not receive sotalol (within-day variability controls). Left ventricular (LV) internal dimension at end-systole normalized to bodyweight (LVIDs_N), LV ejection fraction (LV EF), LV shortening area, LV fractional shortening, tricuspid annular plane systolic excursion (TAPSE), and right ventricular systolic myocardial velocity were evaluated as indices of systolic function. RESULTS: All indices except TAPSE had mild decreases in systolic function post-sotalol (all P ≤ .0007) compared with baseline but only the percent change in LVIDs_N and LV EF were significantly (P ≤ .0079) different from the percent change of the same indices in control dogs. Sinus heart rate, ventricular premature complexes/5-minutes, and arrhythmia grade also were decreased post-sotalol (all P ≤ .01) compared with baseline when assessed by a 5-minutes ECG. No dog experienced an adverse event post-sotalol, including dogs with systolic dysfunction or atrial enlargement. CONCLUSIONS AND CLINICAL IMPORTANCE: A single dose of sotalol may cause a mild decrease in LV systolic function in dogs with ventricular arrhythmias. Sotalol appears to be well tolerated, even in dogs with atrial enlargement or systolic dysfunction.
Assuntos
Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/veterinária , Doenças do Cão/tratamento farmacológico , Ecocardiografia/veterinária , Sotalol/uso terapêutico , Função Ventricular/efeitos dos fármacos , Animais , Arritmias Cardíacas/diagnóstico por imagem , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/fisiopatologia , Doenças do Cão/diagnóstico por imagem , Doenças do Cão/fisiopatologia , Cães , Feminino , Frequência Cardíaca/efeitos dos fármacos , Masculino , Volume Sistólico/efeitos dos fármacos , Sístole/efeitos dos fármacos , Função Ventricular/fisiologiaRESUMO
OBJECTIVES: We aimed to evaluate safety and efficacy of high-pressure balloon valvuloplasty (HPBVP) for treatment of canine severe pulmonary valve stenosis (PS). A secondary aim was to provide pre-procedure predictors of success. ANIMALS: Twenty-five dogs. METHODS: Prospective observational study. Dogs with severe PS (echocardiographically derived trans-pulmonary peak/maximum pressure gradient (EDPG) ≥80 mmHg) were recruited. All dogs underwent echocardiography before and 20-24hrs after HPBVP using a high-pressure balloon with rated burst pressures ranging from 12 to 18 ATM. Procedural success was defined as a post-HPBVP EDPG reduction of ≥50% or reduction into at least the moderate category of PS (50-79 mmHg). Optimal result was defined as a post-procedural EDPG ≤30 mmHg. RESULTS: Initial median (IQR) EDPG for all dogs was 96 (88, 127) mmHg with a post-operative median of 48 (36, 65) mmHg. The median EDPG reduction provided by HPBVP was 63% (39, 68); procedural success rate was 92% (23 dogs). Optimal results were achieved in 56% (14 dogs). There were no significant correlations between EDPG reduction and valve morphology (Type A and Type B) or severity of right ventricular hypertrophy. Pulmonary valve annulus diameter was the only echocardiographic variable that was significantly correlated to EDPG reduction (p = 0.02; r = -0.46). No dog experienced any anesthetic or surgical complications, and all patients survived the procedure. CONCLUSIONS: In this cohort of 25 dogs with severe PS, HPBVP was safe and effective. The procedural success rate and high number of optimal results achieved with HPBVP suggest future randomized controlled trials comparing HPBVP to conventional valvuloplasty are warranted.
Assuntos
Valvuloplastia com Balão/veterinária , Doenças do Cão/terapia , Estenose da Valva Pulmonar/veterinária , Animais , Valvuloplastia com Balão/métodos , Pressão Sanguínea , Doenças do Cão/congênito , Cães , Ecocardiografia/veterinária , Projetos Piloto , Estudos Prospectivos , Estenose da Valva Pulmonar/congênito , Estenose da Valva Pulmonar/terapia , Resultado do TratamentoRESUMO
[This corrects the article DOI: 10.1371/journal.pone.0209112.].
RESUMO
INTRODUCTION: Golden retrievers are over-represented in cases of taurine-deficient dilated cardiomyopathy and recently a surge in cases has prompted further investigation. OBJECTIVE: To describe the clinical, dietary, and echocardiographic features in golden retrievers diagnosed with taurine deficiency and dilated cardiomyopathy, and to determine specific dietary associations. A second aim was to determine the whole blood taurine concentrations in a representative sample of healthy golden retrievers. ANIMALS: Twenty-four client-owned golden retrievers with documented taurine deficiency and dilated cardiomyopathy and 52 healthy client-owned golden retrievers. METHODS: In this multicenter prospective observational study, baseline and follow-up echocardiographic data, complete diet and medical histories, and whole blood, plasma, or serum taurine concentrations were obtained. Baseline and follow-up echocardiographic data were compared. Associations were evaluated between specific diets and taurine deficiency or congestive heart failure. The prevalence of low whole blood taurine concentrations in the healthy golden retrievers was calculated. RESULTS: Twenty-three of 24 dogs diagnosed with taurine deficiency and dilated cardiomyopathy were fed diets that were either grain-free, legume-rich, or a combination of these factors. None of these diets were feeding trial tested using Association of American Feed Control Officials (AAFCO) procedures. Twenty-three of 24 dogs had significant improvement in their echocardiographic parameters and normalization of taurine concentrations following diet change and taurine supplementation. Nine of 11 dogs diagnosed with congestive heart failure (CHF) had resolution of their congestion at follow-up with five no longer requiring diuretic therapy and four tolerating diuretic dose reduction by >50%. CONCLUSIONS: Certain diets and diet characteristics were associated with the development of taurine deficiency. Taurine deficiency and dilated cardiomyopathy in golden retrievers is likely multifactorial, including a combination of dietary, metabolic, and genetic factors.
Assuntos
Cardiomiopatia Dilatada/diagnóstico , Dieta/efeitos adversos , Doenças do Cão/diagnóstico , Taurina/metabolismo , Ração Animal/efeitos adversos , Fenômenos Fisiológicos da Nutrição Animal , Animais , Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/fisiopatologia , Dieta/veterinária , Doenças do Cão/etiologia , Doenças do Cão/fisiopatologia , Cães , Ecocardiografia , Grão Comestível/efeitos adversos , Feminino , Coração/diagnóstico por imagem , Coração/fisiopatologia , Masculino , Taurina/deficiência , Taurina/genéticaRESUMO
Fibril formation of amyloid beta peptide (Abeta) is considered to be responsible for the pathology of Alzheimer's disease (AD). The Abeta fibril is formed by a protein misfolding process in which intermolecular beta-sheet interactions become stabilized abnormally. Thus, to develop potential anti-AD drugs, we screened an in-house library to find compounds which have a profile as a beta-sheet breaker. We searched for a beta-sheet breaker profile in an in-house library of approximately 113,000 compounds. From among the screening hits, we focused on N,N'-bis(3-hydroxyphenyl)pyridazine-3,6-diamine (named RS-0406), which had been newly synthesized in our laboratory. This compound (10-100 microg ml(-1)) was found to be capable of significantly inhibiting 25 microM Abeta(1-42) fibrillogenesis and, furthermore, disassembling preformed Abeta(1-42) fibrils in vitro. 3 We then investigated the effect of RS-0406 on 111 nM Abeta(1-42)-induced cytotoxicity in primary hippocampal neurons, and found that 0.3-3 microg ml(-1) RS-0406 ameliorates the cytotoxicity. Moreover, 3 microg ml(-1) RS-0406 reversed 1 micro M Abeta(1-42)-induced impairment of long-term potentiation in hippocampal slices. 4 In this study, we have succeeded in identifying RS-0406 which has potential to inhibit Abeta(1-42) fibrillogenesis, and to protect neurons against Abeta(1-42)-induced biological toxicity in vitro. These results suggest that RS-0406 or one of the derivatives could become a therapeutic agent for AD patients.
Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/toxicidade , Diaminas/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/toxicidade , Piridazinas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Células Cultivadas , Diaminas/química , Diaminas/uso terapêutico , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Estrutura Secundária de Proteína/efeitos dos fármacos , Estrutura Secundária de Proteína/fisiologia , Piridazinas/química , Piridazinas/uso terapêutico , Ratos , Ratos WistarRESUMO
Amyloid beta-peptide (Abeta) effectively inhibits the cellular reduction activity of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) in a variety of cultured cells. Although the inhibitory activity is widely used for the estimation of the biological activity of Abeta, the cellular mechanism is unclear. In the present study, we examined the effect of Abeta on the morphology of early endosomes, in which MTT is accumulated as MTT formazan after cellular reduction. We found that Abeta1-40 alters the distribution of Rab5- and early endosomal auto-antigen 1-positive early endosomes in the presence of MTT in HeLa cells, which are susceptible to the Abeta1-40-induced inhibition of cellular MTT reduction. To obtain a clue to the molecular mechanism, we determined whether Abeta1-40 affects the signal cascade of the phosphatidylinositol-3-OH kinase (PI-3K) pathway that is involved in early endosomal trafficking. MTT induced phosphorylation of Akt and mitogen-activated protein kinase. Abeta1-40 suppressed the PI-3K-dependent Akt phosphorylation but not the mitogen-activated protein kinase phosphorylation. Thus, Abeta seems to modulate early endosomal trafficking via inhibition of the PI-3K pathway in the presence of MTT. Modulation of early endosomal trafficking appears to affect the cellular metabolism of MTT, causing suppression of cellular MTT reduction by Abeta. These findings may help clarify the mechanism of the cytotoxicity of Abeta.
Assuntos
Peptídeos beta-Amiloides/farmacologia , Corantes/metabolismo , Endossomos/metabolismo , Fragmentos de Peptídeos/farmacologia , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas/metabolismo , Sais de Tetrazólio/metabolismo , Tiazóis/metabolismo , Anticorpos/metabolismo , Biomarcadores , Cromonas/metabolismo , Inibidores Enzimáticos/metabolismo , Células HeLa , Humanos , Imuno-Histoquímica , Proteínas de Membrana/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Morfolinas/metabolismo , Oxirredução , Fosforilação , Proteínas Proto-Oncogênicas/farmacologia , Proteínas Proto-Oncogênicas c-akt , Proteínas de Transporte Vesicular , Proteínas rab5 de Ligação ao GTP/metabolismoRESUMO
beta-Amyloid peptide is the principal protein in the senile plaques of Alzheimer's disease and is considered to be responsible for the pathology of Alzheimer's disease. Several studies have shown that beta-amyloid is cytotoxic, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as an indicator of viability in cells. Utilizing the MTT assay, we screened an in-house library to find compounds that suppress beta-amyloid-induced inhibition of MTT reduction. From among the screening hits, we focused on 6-ethyl-N,N'-bis(3-hydroxyphenyl)[1,3,5]triazine-2,4-diamine (named RS-0466), which had been newly synthesized in our laboratory. This compound was found to be capable of significantly inhibiting beta-amyloid-induced cytotoxicity in HeLa cells and of reversing the decrease of phosphorylated Akt induced by beta-amyloid. Furthermore, RS-0466 reversed the beta-amyloid-induced impairment of long-term potentiation in rat hippocampal slices. These results raise the possibility that RS-0466 or its derivatives have potential as a therapeutic agent for Alzheimer's disease patients, and its effect is at least in part mediated by activation of Akt.
Assuntos
Peptídeos beta-Amiloides/toxicidade , Fragmentos de Peptídeos/toxicidade , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas/fisiologia , Transdução de Sinais/efeitos dos fármacos , Triazinas/farmacologia , Animais , Células Cultivadas , Corantes , Potenciais Pós-Sinápticos Excitadores , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Humanos , Técnicas In Vitro , Potenciação de Longa Duração/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Fosforilação , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Ratos , Ratos Wistar , Sais de Tetrazólio , Tiazóis , Fatores de Tempo , Triazinas/químicaRESUMO
Sentinel lymph node detection (SLND) with radiocolloid has become widely used for evaluation of nodal metastasis in primary breast cancer. However, the procedure for recurrent breast cancer is not well established. Contralateral axillary node metastasis is uncommon. We report 2 cases of contralateral axillary node metastasis with recurrent breast cancer. In the first case, contralateral node metastasis was found by SLND. In the other case without SLND, contralateral node metastasis developed after resection of local recurrence. FDG-avid contralateral node was pathologically diagnosed as metastasis. The SLND might be useful in patients with local recurrence after conservative breast cancer surgery.
Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Mastectomia Segmentar , Adulto , Axila , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-IdadeRESUMO
To elucidate the function of MAS-related GPCR, member D (MRGD) in cancers, we investigated the in vitro and in vivo oncogenic function of MRGD using murine fibroblast cell line NIH3T3 in which MRGD is stably expressed. The expression pattern of MRGD in clinical samples was also analyzed. We found that overexpression of MRGD in NIH3T3 induced focus formation and multi-cellular spheroid formation, and promoted tumors in nude mice. In other words, overexpression of MRGD in NIH3T3 induced the loss of contact inhibition, anchorage-independent growth and in vivo tumorigenesis. Furthermore, it was found that the ligand of MRGD, beta-alanine, enhanced spheroid formation in MRGD-expressing NIH3T3 cells. From investigation of clinical cancer tissues, we found high expression of MRGD in several lung cancers by immunohistochemistry as well as real time PCR. Based on these results, MRGD could be involved in tumorigenesis and could also be a novel anticancer drug target.
Assuntos
Transformação Celular Neoplásica/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/biossíntese , Receptores Acoplados a Proteínas G/biossíntese , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Feminino , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células NIH 3T3 , Proteínas de Neoplasias/genética , Receptores Acoplados a Proteínas G/genéticaRESUMO
Abnormal behaviors and death associated with the use of oseltamivir (Tamiflu) have emerged as a major issue in influenza patients taking the drug. Here, we investigated the mechanisms underlying the effects of oseltamivir on the behavior of mice using light-dark and open-field preference tests. Oseltamivir (75 and 150 mg/kg, intraperitoneally (i.p.)) alone affected neither time spent in the open area in the light-dark preference test nor ambulation in the open-field test at 2h post-injection. However, a non-selective adenosine A(1)/A(2) receptor antagonist, caffeine (10mg/kg, i.p.) in combination with oseltamivir (150 mg/kg, i.p.) increased time spent in the open area in the light-dark preference test. This enhancement was not inhibited by a benzodiazepine receptor antagonist, flumazenil (10-20mg/kg, subcutaneously (s.c.)). Enhancement of ambulation in the open-field test was also observed when caffeine (10mg/kg, i.p.) was combined with oseltamivir (150 mg/kg, i.p.). This enhancement was inhibited by a dopamine D(2) receptor antagonist, haloperidol (0.1mg/kg, s.c.). Furthermore, an adenosine A(2) receptor antagonist, SCH58261 (3mg/kg, i.p.) in combination with oseltamivir (150 mg/kg, i.p.) increased ambulation in the open-field test, while an adenosine A(1) receptor antagonist, DPCPX (1-3mg/kg, i.p.) did not. These findings suggest that the actions of oseltamivir may involve the dopamine and adenosine systems. Our findings suggest that due to the interaction between central blockade of adenosine A(2) receptors by caffeine, and oseltamivir-induced behavioral changes, patients being treated with oseltamivir should be closely monitored.
Assuntos
Antivirais/farmacologia , Cafeína/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Neurotransmissores/farmacologia , Oseltamivir/farmacologia , Antagonistas do Receptor A1 de Adenosina , Antagonistas do Receptor A2 de Adenosina , Animais , Antivirais/administração & dosagem , Escuridão , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Flumazenil/administração & dosagem , Flumazenil/farmacologia , Moduladores GABAérgicos/administração & dosagem , Moduladores GABAérgicos/farmacologia , Antagonistas de Receptores de GABA-A , Haloperidol/farmacologia , Masculino , Camundongos , Oseltamivir/administração & dosagem , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Distribuição Aleatória , Triazóis/administração & dosagem , Triazóis/farmacologia , Xantinas/administração & dosagem , Xantinas/farmacologiaRESUMO
The lag between beta-amyloid (A beta) deposition and neurodegeneration in Alzheimer's disease (AD) suggests that age-dependent factors are involved in the pathogenesis. Racemization of Ser and Asp in A beta is a typical age-dependent modification in AD. We have shown recently that A beta1-40 racemized at Ser(26) ([D-Ser(26)]A beta 1-40) is soluble and non-toxic to neuronal cells, but is easily converted by brain proteases to truncated toxic fragments, [D-Ser(26)]A beta 25-35/40. Furthermore, [D-Ser(26)]A beta1-40 in vivo, produced a drastic and synergistic neuronal loss by enhancing the excitotoxicity when co-injected into rat hippocampus with ibotenic acid, an excitatory amino acid, suggesting an in vivo conversion of non-toxic [D-Ser(26)]A beta1-40 to toxic fragments including [D-Ser(26)]A beta 25-35/40. In this study, we further investigated the mechanism behind the in vivo neuronal loss by [D-Ser(26)]A beta1-40 and ibotenic acid in rats, and also searched for the presence of [D-Ser(26)]A beta 25-35/40 antigens in AD brains. Quantitative analyses of the damaged area indicate clearly that non-toxic [D-Ser(26)]A beta 1-40 caused as much neurodegeneration as toxic [D-Ser(26)]A beta 25-35/40. MK-801, an NMDA receptor antagonist, completely inhibited the neurodegeneration. The immunohistochemical analyses using anti-[D-Ser(26)]A beta 25-35/40-specific antibodies demonstrated the presence of [D-Ser(26)]A beta 25-35/40 antigens in senile plaques and in degenerating hippocampal CA1 neurons in AD brains, but not in age-matched control brains. These results strengthen our hypothesis that soluble [D-Ser(26)]A beta1-40, possibly produced during aging, is released from plaques and converted by proteolysis to toxic [D-Ser(26)]A beta 25-35/40, which damage hippocampal CA1 neurons by enhancing excitotoxicity in AD. This may account for the lag between A beta deposition and neurodegeneration in AD.
Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Neurônios/metabolismo , Idoso , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Isomerases de Aminoácido/metabolismo , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Ácido Ibotênico , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neurônios/patologia , Neurotoxinas/farmacologia , Células PC12 , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/toxicidade , Placa Amiloide/efeitos dos fármacos , Placa Amiloide/metabolismo , Ratos , Ratos Sprague-Dawley , Serina/metabolismoRESUMO
Amyloid beta peptide in the senile plaques of patients with Alzheimer's disease is considered to be responsible for the pathology of Alzheimer's disease. We have previously reported that 6-ethyl-N,N'-bis(3-hydroxyphenyl)[1,3,5]triazine-2,4-diamine, RS-0466, is capable of significantly inhibiting amyloid beta-induced cytotoxicity in HeLa cells. To determine various profiles of RS-0466, we investigated whether RS-0466 would enhance the neuroprotective effect of brain-derived neurotrophic factor on amyloid beta(1-42)-induced cytotoxicity in rat cortical neurones. Consistent with previous observations, brain-derived neurotrophic factor ameliorated amyloid beta(1-42)-induced cytotoxicity. Furthermore, co-application of RS-0466 enhanced the neuroprotective effect of brain-derived neurotrophic factor. RS-0466 also reversed amyloid beta(1-42)-induced decrease of brain-derived neurotrophic factor-triggered phosphorylated Akt. These results raise the possibility that RS-0466 or one of its derivatives has potential to enhance the neuroprotective effect of brain-derived neurotrophic factor, and could serve as a therapeutic agent for patients with Alzheimer's disease.
Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Córtex Cerebral/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/antagonistas & inibidores , Triazinas/uso terapêutico , Peptídeos beta-Amiloides/toxicidade , Animais , Células Cultivadas , Córtex Cerebral/metabolismo , Fragmentos de Peptídeos/toxicidade , Ratos , Ratos Sprague-DawleyRESUMO
Progressive deposition of amyloid beta peptide in the senile plaques is a principal event in the neurodegenerative process of Alzheimer's disease. Several reports have demonstrated that amyloid beta is cytotoxic using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as an indicator of viability in cells. With the MTT assay, we screened an in-house library to find compounds which suppress amyloid beta-induced inhibition of MTT reduction. We have previously reported that 6-ethyl-N,N'-bis(3-hydroxyphenyl)[1,3,5]triazine-2,4-diamine (named RS-0466), found in an in-house library, was capable of significantly inhibiting amyloid beta-induced cytotoxicity in HeLa cells. From further screening hits, we newly focused on 4-(7-hydroxy-2,2,4-trimethyl-chroman-4-yl)benzene-1,3-diol (named RS-4252), which show comparable potency to RS-0466 to ameliorate amyloid beta-induced cytotoxicity. Furthermore, RS-4252 reversed the decrease in phosphorylated Akt by amyloid beta. These results imply that RS-4252 or one of its derivatives has the potential to be a therapeutic for Alzheimer's disease patients, and that activation of Akt is at least in part involved in the effect.